Mechanisms of brain dysfunction and death due to neurodegenerative diseases of the central nervous system (CNS) are poorly understood, but the emergence of profound cognitive and/or motor impairments in these heterogenous diseases is a manifestation of the progressive and massive degeneration of selectively vulnerable populations of neurons that distinguishes neurodegenerative diseases from normal aging. Additionally, intracellular filamentous inclusions are neuropathological hallmarks of many neurodegenerative diseases despite their heterogeneity. For example, abnormal alpha-synuclein filaments aggregate to form Lewy bodies (Lbs) in neurons and they are signature lesions of Parkinson's disease (PD), dementia with Lbs (DLB) and an Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD), while multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) composed of alpha-synuclein filaments aggregate to form Lewy bodies (Lbs) in neurons and they are signature lesions of Parkinson's disease (PD), dementia with Lbs (DLB) and an Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD), while multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) composed of alpha-synuclein filaments. Although these inclusions often were regarded as epiphenomena unrelated to mechanisms of brain degeneration, this view has undergone dramatic revisions after the discoveries that: mutations in the alpha- synuclein cause familial PD in rare kindreds, alpha-synuclein is a major component of Lbs and GCIs, and wild type, as well as mutant alpha- synuclein form filaments in vitro similar to those in Lbs and GCIs. Moreover, the pressure or abundant alpha-synuclein from filaments in vitro similar to those in Lbs and GCIs. Moreover, the presence of abundant alpha-synuclein Lbs in the most common variant of sporadic AD (i.e., LBVAD), >60% of familial AD brains and >50% of Down's syndrome brains with AD provides an opportunity to elucidate mechanisms of the enigmatic, but frequent overlap of AD and PD. Finally, we also have shown that beta- and gamma-synucleins accumulate in dystrophic overlap of AD and PD. Finally, we also have shown that beta- and gamma-synucleins accumulate in dystrophic hippocampal processes in PD and DLB. Thus, we hypothesize that accumulations of synuclein filaments or aggregates play a mechanistic role in neurodegenerative diseases characterized by abundant synuclein pathology, and this Program Project grant describes four complementary Projects to test this hypothesis with the support of an Administrative,. Clinical, and Neuropathology Core. The Projects are highly synergistic and pursue research conducted on disease brains with authentic human synuclein pathology (Project 1), as well as on mechanisms of synuclein pathologies using in vitro (Project 2), transgenic fly (Project 3) and transgenic mouse (Project 4) models. This Program Project will provide new insights into mechanisms of synuclein pathologies and their role in brain degeneration, which are likely to accelerate efforts to improve the diagnosis and therapy of these and other neurodegenerative disorders characterized by filamentous brain lesions.